POS0051 DIFFERENTIAL PHARMACODYNAMIC ALTERATIONS AFTER TREATMENT WITH ABATACEPT OR ADALIMUMAB IN MTX-INADEQUATE RESPONDER PATIENTS WITH EARLY RA: WHOLE BLOOD RNA-SEQ ANALYSIS OF THE EARLY AMPLE STUDY
Authors: C. Wu, Y. Li, N. Ray, M. A. Maldonado, P. Schafer, S. L. Bridges, W. Rigby, V. Bykerk, J. Buckner, J. Liu
Journal: Annals of the Rheumatic Diseases (2022)

Background Despite advances in available novel pharmacologic agents for RA, 1 the dearth of effective response predictors for specific therapies remains an unmet need. To inform clinical decision making, it is critical to define molecular signatures of these therapeutic agents by investigating their mechanisms of action (MoAs) and differential impacts on patients’ immune systems. Adalimumab and abatacept are biologic DMARDs with distinct MoAs used to treat RA. A better understanding of the differential pharmacodynamic (PD) changes of these 2 agents may provide guidance for the selection of treatment options. 2 The Early AMPLE ( A batacept versus adali M umab com P arison in bio L ogic-naïv E RA subjects with background MTX) study compared treatment with abatacept or adalimumab in a population of patients with early RA to explore differential PD effects; abatacept treatment resulted in numerically higher efficacy responses vs adalimumab after 24 weeks of treatment. 3 Objectives To investigate PD changes in response to treatment with abatacept or adalimumab, and to identify and differentiate the impact of each drug on modulation of immune cells at the molecular level. Methods The phase 4 Early AMPLE trial ( NCT02557100 ) was a head-to-head comparison of treatment response to either abatacept or adalimumab in patients with early RA with an inadequate response to MTX, high anti-citrullinated protein antibody titers, and RF positivity, with or without shared epitope. Whole blood RNA sequencing (RNA-Seq) was conducted on samples collected from patients at different visits (day 1; weeks 4, 8, 16, 24, 28, 32, 40, 48). Differential gene expression analyses were performed using Limma-voom pipeline in R, adjusting for batch effect and sex. Over-representation tests were used to identify enriched Gene Ontology pathways. xCell, a gene signatures–based method learned from thousands of pure cell types, was applied for immune cell type deconvolution and enrichment analysis. Results PD and association analyses were performed for 14,540 protein-coding genes in 664 RNA-Seq samples (79 patients with RA at 9 visits). Baseline association analysis showed that 248 differentially expressed genes and 6 cell cycle–related pathways were significantly associated with baseline SDAI score. After treatment, gene-enrichment analysis demonstrated that twice as many genes and pathways were significantly altered in the adalimumab- vs abatacept-treated arm. Abatacept treatment decreased immune cell cycle gene expression while adalimumab treatment increased expression of these genes. The increases due to adalimumab were reversed after switching to abatacept (open-label period). Using gene signatures to identify key immune cell subsets (Figure 1), adalimumab therapy increased expression of genes defining several key immune cell types involved in RA disease development, including dendritic cells, T cells, and B cells; these effects were also reversed after switching to abatacept. Conclusion The differential gene expression seen after treatment with abatacept or adalimumab was noted in genes identified as correlating with RA disease activity. These findings may inform on the mechanism for the relatively greater clinical improvements seen with abatacept vs adalimumab in the Early AMPLE study. Abatacept treatment may selectively modulate genes that are relevant to disease pathology/progression, with the potential to restore the immune homeostasis dysregulated in RA. Our findings warrant further studies to investigate the potential positive correlation between RA-relevant PD effects and better therapeutic outcomes. References [1]Mysler E, et al. Open Access Rheumatol 2021;13:139–52. [2]van Vollenhoven R. Nat Rev Rheumatol 2019;15:180–6. [3]Rigby W, et al. Arthritis Res Ther 2021;23:245. Acknowledgements This study was sponsored by Bristol Myers Squibb. Medical writing and editorial assistance were provided by Joanna Wright, DPhil, of Caudex, and was funded by Bristol Myers Squibb. Disclosure of Interests Chun Wu Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Yicong Li Consultant of: Bristol Myers Squibb, Employee of: Parexel International, Neelanjana Ray Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Michael A Maldonado Employee of: Bristol Myers Squibb, Peter Schafer Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, S. Louis Bridges Grant/research support from: Bristol Myers Squibb, William Rigby Consultant of: AbbVie, Bristol Myers Squibb, Grant/research support from: AbbVie, Bristol Myers Squibb, Vivian Bykerk Consultant of: Amgen, Bristol Myers Squibb, Genzyme Corporation, Gilead, Regeneron, UCB, Grant/research support from: Amgen, Bristol Myers Squibb, Genzyme Corporation, Pfizer, Regeneron, Sanofi Aventis, UCB, Jane Buckner Consultant of: Bristol Myers Squibb, Hotspot Therapeutics, Janssen, Grant/research support from: Current: Bristol Myers Squibb, GentiBio; past: Amgen, Janssen, Novo Nordisk, Pfizer, Jinqi Liu Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb